This invention relates to a composition and oral pharmaceutical dosage form for selective delivery of drugs to the colon. More particularly, the invention relates to compositions and oral pharmaceutical dosage forms for release of biologically active ingredients in the colon while avoiding or minimizing release into the upper gastrointestinal tract, such the stomach and small intestine.
Numerous drug entities based on oral delivery have been successfully commercialized, but many others are not readily available by oral administration, which are incompatible with the physical and/or chemical environments of the upper GI tract and/or demonstrate poor uptake in the upper GI tract. Due to the lack of digestive enzymes, colon is considered a suitable site for the absorption of various drugs. However, colon drug delivery is hardly achieved in that the oral dosage form should pass through the stomach and small intestine, where many drugs are deactivated by their digestive materials. Ideally, a colon specific drug delivery system is designed such that it remains intact in stomach and small intestine but releases encapsulated drugs only in colon. CSDS system is useful in administering a drug that is an irritant to the upper GI tract, such as non-steroidal anti-inflammatory agents, or drugs that are degraded by gastric juice or an enzyme present in the upper GI tract, such as peptide or protein. Further, the colonic drug delivery system allows local, direct treatment of colonic disease, e.g., ulcerative colitis, Crohn""s disease, or colon cancer, thus reducing the dosage of the drugs and minimizing undesirable or harmful side effects. Similarly, colonic drug delivery is useful for administering drugs, e.g. non-steroidal anti-inflammatory drugs (NSAIDS), which are irritants to the mucosa of the upper gastrointestinal tract such as the stomach or small intestine. Recently, it is believed that colonic drug delivery systems maintain the efficacy of drugs for a longer time and increase the bioavailability of the drugs as compared to other oral routes of administration. As the colon has a longer retention time, drug absorption is prolonged, and total bioavailability is increased. A. Sintov et al., 143 Int. J. Pharma. 101-106 (1996).
Although colon is attracting interest as a site for delivering several drugs such as unstable drugs in upper GI tract or poorly-absorbed drugs, it is very difficult to diver the drug into colon effectively. In order to deliver a drug to the colon selectively, a composition generally should meet the following requirements: (1) the composition is not degraded or disintegrated in the upper GI tract; (2) the composition does not release the loaded drug in the upper GI tract; (3) the composition releases the drug effectively at the target site, the colon, more particularly the ascending colon; and (4) the composition is easy to formulate in a form suitable for loading the drug. Further, the composition preferably can be easily processed for manufacture.
Several approaches have been used in developing colon-specific drug delivery systems. One is based on the different pH of each compartment of the gastrointestinal tract, with the pH of the proximal GI tract being lower than that of the distal GI tract. Thus, polymers that are insoluble at low pH and soluble at higher pH have been used to deliver drugs to the distal GI tract
Another approach is based on the fact that transit time through the stomach is approximately 2 hours, whereas transit time through the small intestine is approximately 4-6 hours. Thus, in this approach, the delivery system is designed to withhold the release of the drugs for about 6-8 hours from the time of administration.
Moreover, it is well known that enzymes capable of reducing azo bonds or hydrolyzing glycosidic bonds, which are not degraded in the stomach and small intestine, are present in the colon. Thus, many approaches to colonic drug delivery use azo bond-containing polymers (azo polymers) or glycosidic bond-containing materials. The glycosidic bond-containing polymers include disaccharides, oligosaccharides, and polysaccharides.
For example, U.S. Pat. No. 5,482,718; U.S. Pat. No. 4,627,851; U.S. Pat. No. 4,693,895; U.S. Pat. No. 4,705,515; U.S. Pat. No. 4,904,474; EP 621 032 A1; JP 34929/1991A; U.S. Pat. No. 5,536,507; EP 453 001 A1; U.S. Pat. No. 5,171,580; and EP 572 942 A2 disclose time dependent drug delivery system. They are designed to prevent drug release for a period of time expected to be sufficient for the composition to pass through the upper gastrointestinal tract. Further, U.S. Pat. No. 5,401,512; U.S. Pat. No. 5,541,170;and WO 95/11024 describe drug compositions for selectively releasing the drug in the colon by way of exploiting the difference in pH between the colon and other parts of the GI tract.
The above-mentioned compositions, however, are not effective in delivering the drug to the colon. The pH in the terminal ileum and colon is higher than other region of the GI tract and thus composition which disintegrate at high pH level have the potential for site specific delivery into this region. However, because the pH is higher in the terminal ileum region than in the colon, and the dosage forms are often delayed at the ileo-cecal junction, the dosage forms based on pH dependent system are often disintegrate in the terminal ileum instead of disintegrate in colon. Further, the colon specific delivery based on GI transit time-dependent system is hardly to be achieved. The transit time in the upper gastrointestinal tract tends to be highly variable among individuals.
Many approaches to colonic drug delivery use azo bond or glycosidic bond-containing drugs, i.e. prodrug and have been successfully come into the market. The prodrug that is activated only in the colon requires covalent bonding between the drug molecule and carrier molecules such that the covalent bonds are broken only by enzymes produced by colonic bacteria. WO 84/04041, WO 93/22334; A. D. McLeod et al., 83 J. Pharm. Sci. 1284-1288(1994); D. R. Friend et al., 27 J. Med. Chem. 261-266 (1984); B. Haeberlin et al., 10 Pharm. Res. 1553-1562 (1993); D. R Friend et al. 28 J. Med. Chem. 51-57 (1985); DR Friend, 5 S.T.P. Pharma Sci. 70-76 (1995); J. P. Brown et al., 26 J. Med. Chem. 1300-1307(1983).
It is well known that enzymes capable of breaking an azo, disulphide bonds and glycosidic bond are present in the colon, but not in the upper GI tract. WO 91/16057 and EP 398 472 A2 disclose compositions containing an azo polymer having azo bonds as a colonic drug delivery system. Although the composition is relatively stable in the upper gastrointestinal tract, the dosage form coated by azo polymer does not showed colon specificity effectively. Azo reductase produced by colonic microflora cannot easily reach the azo bond of azo-polymers due to the hydrophobic nature of the azo-polymer, thus resulting in slow degradation in the colon of the composition containing the azo polymer. P. Y. Yeh et al., 196 Macromol. Chem. Phys. 2183-2202 (1995).
A number of delivery systems based on polysaccharides which are selectively degraded by colonic enzyme have been reported, since polysaccharides are natural polymers with proven final toxicity
U.S. Pat. No. 5,505,966 discloses a pharmaceutical composition containing calcium pectinate as a major component and a filler such as pectin, dextran, avicel, or mixture thereof. U.S. Pat. No. 5,525,634 discloses a pharmaceutical composition containing a synthetic or natural polymer that is degradable by a colonic enzyme, herein calcium pectinate is disclosed as an example of a natural polymer.
In U.S. Pat. No. 5,505,966, the calcium pectinate composition is used in the form of a coacervate pellet. It is believed that calcium pectinate, which is insoluble in water, is converted to a water-soluble matrix by sodium ions or potassium ions present in the digestion solution of upper GI. Therefore, the system mainly depends on transit time of upper GI, thus the pellets often disintegrate and release the drug in upper GI.
U.S. Pat. No. 5,525,634 suggests a compressed tablet formulation that is prepared by pulverizing and compressing a pharmaceutical composition containing a drug and calcium pectinate. In the composition, the strength of compression largely affects the system disintegration through the GI tract. The weak compressed tablet disintegrates easily in the upper gastrointestinal tract by converting to a water-soluble matrix, which caused by sodium ions or potassium ions present in the digestion solution of upper GI. Further, the strongly compressed tablet is hardly disintegrated in colon. Therefore, the compositions disclosed in both U.S. Pat. No. 5,505,966 and U.S. Pat. No. 5,525,634 is highly dependent on the system swelling and on the transit time through the upper gastrointestinal tract, and not on unique characteristics of the composition.
To solve the above problem, Adkin, D. A. et al. suggests the addition of guar gum or pectin as a binder of calcium pectinate compressed tablets and coating them with enteric material. Adkin, D. A. et al. 14 Pharm. Res. 103-107 (1997). Guar gum or pectin is used as a binder for preventing easy disintegration in upper GI and resulted in sustained release effect in colon. Enteric coating is also used for preventing the rapid swelling and disintegration in upper GI. However this system also present slow release of drug in colon and is highly dependent on the enteric coating thickness and on the transit time through the upper gastrointestinal tract, and not on unique characteristics of the composition.
U.S. Pat. No. 4,432,966 discloses a composition comprising microcrystalline cellulose and ethyl cellulose; EP 627 173 A1 describes a cellulose composition; WO 95/35100 discloses a starch capsule and a composition comprising an enteric coating; U.S. Pat. No. 5,422,121 discloses a composition comprising a guar gum or locust bean gum blended with a film forming material. The latter composition is formulated by using polysaccharide with the film forming materials. Generally polysaccharides have the hydrophilic moiety and have a difficulty in fabricating the coating film in the coated dosage form due to its physical properties. In addition, the polysaccharide films and matrix fabricated by compression method, they are easily disintegrated in upper GI. Therefore, polysaccharides are mixed with the more hydrophobic film-forming material in the above-mentioned composition. Although the blend of polysaccharide and film forming material shows the improved film forming properties, a hydrophobic film-forming material generally has the lower swelling ratio than that of a polysaccharide. Due to the swelling ratio difference, the coated film comprising a polysaccharide and a film forming material is often phase-separated and bring a crack during passage through the stomach and small intestine. In addition, the using hydrophobic film forming material bring the undesirable result that disintegration of dosage form by colonic enzyme is delayed due to the hydrophobic nature of the mixed polymer, thus resulting in slow degradation in the colon of the composition. It may be happened that colonic enzyme from microflora cannot easily reach the polysaccharide due to the hydrophobic nature of the mixed polymer. Accordingly, the drug is often released in the upper gastrointestinal tract, or it is so slow drug release that the system fails to show colon specific drug delivery. In view of the foregoing, it will be appreciated that providing a polysaccharide-based composition for controlled drug delivery in the colon would be a significant advancement in the art.
An object of the present invention is to provide a composition and pharmaceutical dosage form for delivering a drug, wherein such dosage form is orally-administered for specifically delivering the drug to the colon of a subject in need thereof.
Another object of the invention is to provide a composition and pharmaceutical dosage form for colonic drug delivery that is not degraded or disintegrated in the upper GI tract.
Still another object of the invention is to provide a composition and pharmaceutical dosage form for delivering an orally-administered drug is that is inactivated in the upper GI tract, wherein the dosage form is in a form that passes through the upper GI tract and then releases the drug in the colon of a human subject in need thereof.
Yet another object of the invention is to provide a composition and pharmaceutical dosage form for colonic drug delivery that releases the drug rapidly and effectively at the target site, the colon, and minimizes adverse systemic effects to a subject being treated.
Another object of the invention is to provide a composition and pharmaceutical dosage form for colonic drug delivery that is easy to formulate in a form suitable for loading the drug to be delivered.
Still another object of the invention is to provide a method for treating a subject through oral administration of a pharmaceutical dosage form and composition that achieves the foregoing objects of this invention.
Yet another object of the invention is to provide a process for preparing a pharmaceutical dosage form and composition that achieves the forgoing objects of this invention.
One aspect of this invention is a composition and pharmaceutical dosage form designed for delivering an orally administered drug to the colon. The composition passes through the upper GI tract without releasing the drug, but the drug is rapidly and effectively released at the target site in the colon, more especially in the ascending colon, minimizing adverse systemic effects to a human subject being treated. The composition comprises a mixture, prepared at a pH of about 7 or above, without use of a cross-linking agent, of a galactomannan and a polysaccharide, preferably pectin, selected from the group consisting of pectin, derivatives of pectin, and mixtures thereof. The composition forms a strong elastic gel that is not appreciably dissolved or disintegrated in gastric or intestinal fluids, thus protecting drugs from being released in the upper GI tract. When the composition arrives in the colon, the composition is easily degraded by synergic effect of pectinolytic enzymes and glactomannanase, thus releasing drugs rapidly in the colon. The ratio of the two polysaccharides determines the rate of enzymatic degradation of the composition and disintegration of dosage form through GI tract, which in turn enables the composition to release the drug site specifically in the colon. More particularly, the ratio and coating thickness of the two
Another aspect of this invention provides a colon specific composition and a pharmaceutical dosage form comprising the inventive colonic drug delivery composition and a biologically active substance without additional enteric coating and an independence to individual variance such as pH and transit time. The composition and dosage form of this invention can be in form of a coating material, hard capsule shell material, or matrix.